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Silica nanoparticles induce hepatocyte ferroptosis and liver injury via ferritinophagy
Environmental Science: Nano ( IF 7.3 ) Pub Date : 2022-07-06 , DOI: 10.1039/d2en00116k Qingqing Liang , Yuexiao Ma , Fenghong Wang , Mengqi Sun , Linsen Lin , Tianyu Li , Zhiwei Sun , Junchao Duan
Environmental Science: Nano ( IF 7.3 ) Pub Date : 2022-07-06 , DOI: 10.1039/d2en00116k Qingqing Liang , Yuexiao Ma , Fenghong Wang , Mengqi Sun , Linsen Lin , Tianyu Li , Zhiwei Sun , Junchao Duan
As one of the most mass-produced and extensively used engineered nanomaterials, silica nanoparticles (SiNPs) have gained attention due to their environmental health and safety (EHS) concerns because of the increasing exposure hazards to environment and human beings. SiNPs have been reported to induce liver toxicity, but its potential mechanism has not been fully clarified. The purpose of this study was to investigate whether SiNPs caused hepatocyte ferroptosis and liver injury via ferritinophagy. In the in vivo study, SiNPs led to histopathological damage in liver, accompanied by hepatocellular ferroptosis, which was characterized by lipid peroxidation and ferritinophagy. In vitro, SiNPs could trigger ferroptosis in L-02 cells, as evidenced by the cell viability reduction, mitochondrial membrane/cristae rupture, phospholipid hydroperoxides (PL-OOH) aggravation, mitochondrial/intracellular free ferrous iron accumulation, and lipid peroxidation repair capacity impairment. Importantly, ferrostatin-1 (Fer-1) rescued the SiNP-induced cytotoxiciy and lipid peroxidation. Further, SiNPs caused the complete ferritinophagy process from autophagosomes containing ferritin formation to degradation. Notably, bafilomycin A1 (BafA1) caused the further accumulation of autophagosomes containing ferritin induced by SiNPs. Interestingly, NCOA4 knockdown inhibited the degradation of ferritin, reduced the intracellular free ferrous iron, alleviated lipid peroxidation and its repair capacity impairment, and finally decreased SiNP-caused cell death. In addition, the ratio of autophagosome accumulation caused by the inhibition of ferritinophagy to autophagy was estimated to be 53%. In summary, our data suggested that NCOA4-mediated ferritinophagy, as an important form of autophagy induced by SiNPs, was a novel mechanism for SiNP-motivated hepatocyte ferroptosis and liver injury, which was reported for the first time.
中文翻译:
二氧化硅纳米粒子通过铁蛋白吞噬诱导肝细胞铁死亡和肝损伤
作为最大规模生产和广泛使用的工程纳米材料之一,二氧化硅纳米粒子(SiNPs)由于其对环境和人类的暴露危害越来越大,因其对环境健康和安全(EHS)的关注而受到关注。据报道,SiNPs 会引起肝毒性,但其潜在机制尚未完全阐明。本研究的目的是调查 SiNPs 是否通过铁蛋白吞噬引起肝细胞铁死亡和肝损伤。在体内研究中,SiNPs 导致肝脏组织病理学损伤,并伴有以脂质过氧化和铁蛋白吞噬为特征的肝细胞铁死亡。体外, SiNPs 可引发 L-02 细胞中的铁死亡,这可以通过细胞活力降低、线粒体膜/嵴破裂、磷脂氢过氧化物 (PL-OOH) 加重、线粒体/细胞内游离亚铁积累和脂质过氧化修复能力受损来证明。重要的是,ferrostatin-1 (Fer-1) 挽救了 SiNP 诱导的细胞毒性和脂质过氧化。此外,SiNPs 引起了从含有铁蛋白的自噬体形成到降解的完整的铁蛋白吞噬过程。值得注意的是,巴弗洛霉素 A1 (BafA1) 引起了由 SiNPs 诱导的含有铁蛋白的自噬体的进一步积累。有趣的是,NCOA4 敲低抑制了铁蛋白的降解,减少了细胞内的游离亚铁,减轻了脂质过氧化及其修复能力的损害,最后减少了 SiNP 引起的细胞死亡。此外,抑制铁蛋白吞噬引起的自噬体积累与自噬的比例估计为 53%。总之,我们的数据表明,NCOA4介导的铁蛋白吞噬作为SiNPs诱导的一种重要自噬形式,是SiNPs诱导的肝细胞铁死亡和肝损伤的一种新机制,这是首次报道。
更新日期:2022-07-06
中文翻译:
二氧化硅纳米粒子通过铁蛋白吞噬诱导肝细胞铁死亡和肝损伤
作为最大规模生产和广泛使用的工程纳米材料之一,二氧化硅纳米粒子(SiNPs)由于其对环境和人类的暴露危害越来越大,因其对环境健康和安全(EHS)的关注而受到关注。据报道,SiNPs 会引起肝毒性,但其潜在机制尚未完全阐明。本研究的目的是调查 SiNPs 是否通过铁蛋白吞噬引起肝细胞铁死亡和肝损伤。在体内研究中,SiNPs 导致肝脏组织病理学损伤,并伴有以脂质过氧化和铁蛋白吞噬为特征的肝细胞铁死亡。体外, SiNPs 可引发 L-02 细胞中的铁死亡,这可以通过细胞活力降低、线粒体膜/嵴破裂、磷脂氢过氧化物 (PL-OOH) 加重、线粒体/细胞内游离亚铁积累和脂质过氧化修复能力受损来证明。重要的是,ferrostatin-1 (Fer-1) 挽救了 SiNP 诱导的细胞毒性和脂质过氧化。此外,SiNPs 引起了从含有铁蛋白的自噬体形成到降解的完整的铁蛋白吞噬过程。值得注意的是,巴弗洛霉素 A1 (BafA1) 引起了由 SiNPs 诱导的含有铁蛋白的自噬体的进一步积累。有趣的是,NCOA4 敲低抑制了铁蛋白的降解,减少了细胞内的游离亚铁,减轻了脂质过氧化及其修复能力的损害,最后减少了 SiNP 引起的细胞死亡。此外,抑制铁蛋白吞噬引起的自噬体积累与自噬的比例估计为 53%。总之,我们的数据表明,NCOA4介导的铁蛋白吞噬作为SiNPs诱导的一种重要自噬形式,是SiNPs诱导的肝细胞铁死亡和肝损伤的一种新机制,这是首次报道。